Nitric oxide in the gastrointestinal tract: opportunities for drug development

Abstract

Nitric oxide (NO) plays important roles in gastrointestinal mucosal defence, as well as in the pathogenesis of several gastrointestinal diseases (e.g. irritable bowel syndrome and inflammatory bowel disease). The potent cytoprotective effects of NO have been demonstrated in a range of animal models. However, in some disease states, inhibition of NO synthesis is beneficial. Several attempts have been made to develop drugs for ulcerative and/or inflammatory disorders of the gastrointestinal tract, with varying degrees of success. Covalently linking a NO-releasing group to non-steroidal anti-inflammatory drugs or to drugs used in the treatment of inflammatory bowel disease and irritable bowel syndrome has shown some benefit, although no drug of this type has yet been fully developed. LINKED ARTICLES: This article is part of a themed section on Nitric Oxide 20 Years from the 1998 Nobel Prize. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc.

Figure 1

Upper panel: An NO‐releasing derivative of diclofenac (‘nitrofenac’) significantly accelerated healing of experimentally‐induced gastric ulcers in rats, as compared to the treatment with vehicle or with diclofenac itself. Equimolar doses of diclofenac and nitrofenac were administered once daily to rats over a period of 7 days after ulcer induction. Ten rats per group. *P < 0.05 versus the vehicle‐ and diclofenac‐treated groups. Lower panel: Once daily administration of diclofenac over 7 days resulted in a significant (***P < 0.001) decrease in haematocrit, consistent with the haemorrhagic lesions observed in the GI tract, as compared to the vehicle‐ and nitrofenac‐treated groups. Diclofenac and nitrofenac were administered at equimolar doses (5 and 7.5 mg·kg⁻¹, respectively; n = 10 per group). From Elliott et al. (1995).

Figure 2

Effects of mesalamine (5‐aminosalicylic acid), NO‐releasing mesalamine and NO‐releasing aspirin in a rat model of colitis. Rats treated with TNBS develop severe colitis (upper panel; n = 6 per group). Treatment with an NO‐releasing derivative of mesalamine but not mesalamine itself significantly reduced the severity of colitis and the associated accumulation of granulocytes within the colonic mucosa [lower panel: measured as myeloperoxidase (MPO) activity]. The NO‐releasing derivative of aspirin did not affect colonic damage severity but did significantly reduce colonic tissue MPO activity. *P < 0.05; **P < 0.01 as compared to the corresponding vehicle‐treated group. All drugs were administered at 100 mg·kg⁻¹. This figure constructed from data reported in Wallace et al. (1999).

Figure 3

Effects of treatment with vehicle, mesalamine or NO‐releasing mesalamine on leukocyte adherence to post‐capillary mesenteric venules in rats before (time 0) and after superperfusion of the vessels with formyl‐methionine‐leucine‐phenylalanine (fMLP; 5 μmol·L⁻¹). The test drugs were given at a dose of 100 mg·kg⁻¹ p.o. 1 h before the start of the experiment. Results are expressed as mean ± SEM for six rats per group. *P < 0.05 versus vehicle‐treated. Figure constructed from the data reported in Wallace et al. (1999).